Genetic alterations of retgroviruses have been documented with lentiviruses such as EIAV and the AIDS virus, as well as with murine leukemia viruses (MuLVs). Ecotropic MuLVs undergo recombination with gene sequences of the mouse to generate recombinant viruses termed polytropic or mink cell focus-forming (MCF) viruses, which have frequently been implicated as the proximal agents involved in transformation to malignancy. A major goal of this project is to characterize the recombinant MuLVs and to define their role in disease induction. Initial studies demonstrated that ecotropic viruses which induce distinct types of leukemias (i.e., erythroleukemia vs. lymphocytic leukemia) recombine with distinct mouse genes to generate MCF viruses. We have extended these studies using a novel retrovirus assay to define new major populations of recombinant viruses which were undetected using conventional assays. The new recombinants isolated during erythroleukemia induction exhibited distinctly different infectious properties than those isolated during lymphocytic leukemia induction and, in both cases, represented the overwhelming majority of recombinant viruses present. Additional studies on tissue-specific replication of ecotropic viruses indicated that the site of replication is controlled by multiple sequences of the viruses, and that leukemia induction requires a high level of replication in the oncogenic target tissue only transiently, early after infection. AKR mice exhibit a high level of spontaneous leukemia and express oncogenic recombinant viruses immediately preceding the earliest incidence of leukemia. The recombinants generated in AKR mice are derived by a stepwise recombination mechanism which is not fully understood. We have identified and studied the structure and expression of a new virus in AKR mice which appears to serve as a recombination intermediate in this stepwise process. Our findings have enabled us to arrive at a detailed model for the generation of the oncogenic recombinants.